Are We Making Mountains Out of Molehills?

When most of us think about manufacturing or aseptic processing, we envision large-scale bulk formulation or fills that take longer than 24 hours. But is this what a product looks like for everyone? After all, not every company focuses on large-scale bulk products, some specialize in small-scale products. Does this mean the regulations change if we go from large-scale to small-scale? In other words, are we scaling mountains to meet requirements that do not pertain to molehills?

The goal of an aseptic operation is to prevent the contamination of materials intended to be sterile. This is where process verification testing becomes important. For large-scale automated operations with infrequent operator interventions, determining if the process can produce sterile products requires analyzing large-scale automated media fills that resemble normal production. Small-scale processes using all or partial manual procedures must also be evaluated by process verification testing.

Manual operations present unique operational and evaluation challenges not generally encountered with automated operations. Manual aseptic processes rely heavily on the proficiency of the individual operator. Operations personnel and their activities are generally recognized as the greatest source of microbial contamination during any given process.

Reproducible human performance cannot be assumed over time. In other words, unlike automated processes, humans cannot be “validated.” We can be qualified and tested, but we humans cannot provide the reproducibility of an automated system.

In effect, what does this mean and how can we state that our drug products are safe, pure and effective if we cannot validate the manual or human aspect of our process? To achieve these key regulatory criteria, special attention to operator training and qualifications, as well as length of time away from/or absence from the process must be considered. Operator training should be extensive and include multiple challenges of all critical steps to a point of proficiency. Training must include qualifications not limited to gowning procedures, technique and media challenges. Documentation must include a list of all critical steps trained on, how many times an operator showed proficiency prior to final evaluation and length of time away from the process.

This process takes into account a number of questions:

• Is this product manufactured or processed daily, monthly or as needed by demand?
• What if an operator is away from the manual process for any length of time?
• What steps are needed to ensure the operators retained all critical steps during their time away from the process?
• How is this process documented?

The PDA Education course, “Recommended Practices for Manual Aseptic Processes,” addresses these and other challenges facing operators during smallscale runs. It not only covers the requirements of how to perform a manual aseptic process but also provides students with a hands-on laboratory media challenge. This course is designed for operations personnel who design, perform and evaluate manual aseptic processes—including personnel involved with compounding, filling, packaging and quality assurance operations, and is suitable for supervisors and managers as well as personnel engaged in manual processing operations.